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4 Toxic Effects of Uranium on the Lungs Uranium is a heavy metal, so one needs to consider chemical effects when evaluating its toxicity (see Chapter 6 for a discussion of radiologic effects). In- halation constitutes a major route of human exposure. Therefore, the respiratory system is evaluated here as a potential target organ for toxicity. After aerosolization of DU munitions, uranium oxide aerosols may be in- haled and deposited in the respiratory tract. Particle deposition is determined by physical and chemical properties of the particles and anatomic and physiologic factors, such as ventilation rate and inhalation pathway (nose vs mouth). Spe- cifically, it depends largely on particle size: in general, larger particles are de- posited in the upper respiratory tract or extrathoracic region, which includes nasopharyngeal airways, and smaller particles are carried to the lower respira- tory tract and deposited mainly in bronchioles and alveoli. Larger particles are trapped mostly in the nasopharyngeal region in nose-breathers, but mouth breathing can enhance their entry into and deposition in tracheobronchial and alveolar regions. The clearance of uranium oxide from the lungs occurs by different mecha- nisms and depends on the deposition site. Uranium trioxide acts like a soluble uranyl salt rather than an insoluble oxide; an inhalation study of dogs (Morrow et al. 1972) determined that it is rapidly cleared from the lungs with a biologic half-life of 4.7 d. Uranium dioxide and triuranium octaoxide are less soluble. Because of their high density, particles of these compounds are deposited mostly in the tracheobronchial region, and their clearance occurs primarily by muco- ciliary transport, which leads to ingestion and transport through the gastrointes- tinal tract; only 1-5% of the particles reach the deeper region of the lungs (Harris 1961). Although the more soluble particles may be absorbed into blood, the less soluble particles deposited in alveoli and those transported to tracheobronchial lymph nodes may remain there for years (ATSDR 1999). The biologic half-life of uranium dioxide in the lungs after occupational exposure was estimated by Schieferdecker et al. (1985) to be 109 d. 43
44 Risks to Military Personnel from Exposure to Depleted Uranium HUMAN STUDIES Epidemiologic studies of the respiratory effects of uranium have involved miners and workers in uranium-processing plants (see Table 4-1). Their results are difficult to interpret because of workersâ coexposure to other respiratory toxicants, the grouping of multiple diseases, and inaccuracies in the coding of death certificates for nonmalignant respiratory diseases. Some of the human studies are described briefly below. A study of workers at the Naval Products Division of the United Nuclear Corporation, a nuclear-fuels fabricating company, determined standardized mor- tality ratios (SMRs) and incidence ratios for employees (Hadjimichael et al. 1983). The SMR for all causes in industrial male workers was significantly lower than expected, but there was an excess of deaths due to obstructive pul- monary disease. Of the six people who died from obstructive pulmonary disease, five had emphysema, but smoking information on four of the five was not avail- able. Because emphysema can be caused by smoking, the incomplete informa- tion on smoking prevented adequate interpretation of excess deaths. In another study, 1,484 men employed in uranium mills in the Colorado Plateau were evaluated (Pinkerton et al. 2004). The study determined a signifi- cant increase in mortality from nonmalignant respiratory disease but identified several limitations, including low cohort size, little power to detect a moderately increased risk of some outcomes, inability to estimate individual exposures, and lack of smoking data. Furthermore, positive trends with employment duration were not observed. Other studies of workers at uranium facilities did not find an association between nonmalignant pulmonary diseases and mortality. For example, Dupree- Ellis et al. (2000) compared mortality in 2,514 workers employed during 1942- 1966 at a uranium-processing plant with overall U.S. mortality. They reported an SMR of 0.90 for all causes of death and 1.05 for all cancers. The SMR for respiratory diseases was 0.80. A retrospective cohort mortality study of workers at a facility for production of nuclear fuel (Cragle et al. 1988) found signifi- cantly fewer deaths in many categories of disease, including all respiratory dis- eases. Polednak and Frome (1981) described mortality in a cohort of 18,869 men employed at a uranium conversion and enrichment plant and reported that the causes of particular interest, including respiratory diseases, did not exhibit high SMRs. Lung-cancer mortality has been estimated in a number of cohort studies that included nearly 110,000 uranium-processing workers (see Chapter 6 for discussion); nearly all the studies had null results. A nested case-control study based on the four largest U.S. cohorts did not find an exposure-response rela- tionship. The few positive results, when combined with uncertainties due to lack of smoking data in the studies, mean, however, that the possibility of associa- tions cannot be dismissed.
Toxic Effects of Uranium on the Lungs 45 TABLE 4-1 Standardized Mortality Ratios (95% Confidence Intervals) [and Observed Number of Deaths] from Nonmalignant Respiratory Diseases in Uranium Workers Nonmalignant Study Respiratory Disease Reference Colorado Plateau uranium-mill workers 1.43 (1.16-1.73)  Waxweiler et al. 1983; (with no history of uranium mining) Pinkerton et al. 2004 TEC/Y12 (1943-1947): Oak Ridge 1.10 (0.98-1.22)  Polednak and Frome 1981 uranium conversion and enrichment, all workers TEC/Y12 (1943-1947): Oak Ridge 1.05 (0.87-1.26)  Polednak and Frome 1981 uranium conversion and enrichment, alpha and beta chemistry departments Y12 (1947-1974): Oak Ridge uranium- 0.88 (0.72-1.07)  Checkoway et al. 1988; metal production and recycling Loomis and Wolf 1996 Mallinckrodt uranium-processing 0.80 (0.62-1.01)  Dupree-Ellis et al. 2000 workers Fernald fabrication of uranium products 0.66 (0.50-0.87)  Ritz 1999 a Portsmouth gaseous diffusion 0.46 (0.24-0.79)  Brown and Bloom 1987 Savannah River nuclear-fuel production 0.40 (0.27-0.57)  Cragle et al. 1988 Linde uranium-processing facility 1.02 (0.80-1.29)  Dupree et al. 1987; Teta (1943-1949) and Ott 1988 United Nuclear Corp. nuclear-fuel 3.03 (1.11-6.59)  Hadjimichael et al. 1983 fabricationb Florida phosphate workersb 0.96 (0.82-1.11)  Checkoway et al. 1996 Atomic Weapons Establishment, UK 0.74 (0.40-1.24)  Beral et al. 1988 Springfields, UK, mortalityc 0.79 (0.71-0.87)  McGeoghegan and Binks 2000a Capenhurst, UK 235U enrichment plant 0.70 (0.53-0.92)  McGeoghegan and Binks mortalityc 2000b Total Observed/Expected Casesd 1,407/1,590 a Includes only âSubcohort I,â which consists of those who at some time worked in one of the departments considered to have uranium exposure. b SMRs were similar for white and nonwhite men, so results for combined groups are presented. c Data given only for those classified as radiation workers. d Sums do not include row labled âTEC/Y12 (1943-47): Oak Ridge uranium conversion and enrichment, alpha and beta chemistry departments,â because those workers were already included in TEC/Y12 row for all workers.
46 Risks to Military Personnel from Exposure to Depleted Uranium ANIMAL STUDIES The respiratory effects in rats and mice of exposure to various uranium compounds include nasal irritation (Spiegl 1949) and nasal hemorrhage (Leach et al. 1984). No symptoms appeared after 30 d of exposure to uranium hexafluoride in any species at inhalation concentrations below 3 mg/m3 (Spiegl 1949). In a 30-d inhalation study, Spiegl (1949) exposed dogs, rats, and rabbits to uranium hexafluoride at 20 mg/m3 and found pathologic signs in the lungs typical of hydrogen fluoride poisoning in dying animals. The pulmonary effects included edema, hemorrhage, inflammation, and irritation. Spiegl noted that uranium hexafluoride hydrolysis liberates uranyl fluoride and hydrofluoric acid, which appear to be responsible for toxic effects in the lungs. Uranium hexafluoride toxicity presents a special situation in that the edema induced by hydrofluoric acid could increase the uptake of uranium by facilitating transport across the airway mucosa. Dygert et al. (1949) exposed animals to uranium tetrafluoride at concen- trations of 0.5-25 mg/m3 for 30 d and reported rhinitis in cats and dogs only at the highest exposure. Uranium dioxide and triuranium octaoxide were not asso- ciated with pulmonary toxicity. Lung injury was not observed in rats, rabbits, guinea pigs, or dogs exposed to various uranium compounds at 0.05-10 mg/m3 for 7-13 mo (Cross et al. 1981a,b). In another study, rats, dogs, and monkeys were exposed to uranium dioxide dust at 5 mg/m3 for 5.4 h/d 5 d/wk for 1-5 y (Leach et al. 1970). A total of 446 animals (120 dogs, 31 monkeys, and 295 rats) were used for control and uranium dioxide exposures. No pathologic findings in the lungs were observed in rats and dogs, but monkeys developed patchy, hya- line pulmonary fibrosis, which was minimal after exposure for 3.6 y and pro- gressed with longer exposure (up to 4.7 y). Mitchel et al. (1999) exposed Spra- gue-Dawley rats to uranium dust at 19 and 50 mg/m3 for 4.2 h/d 5 d/wk for 65 wk and calculated the absorbed dose (in grays) to the lungs. Lung-tumor fre- quency was not directly proportional to dose, but a linear relationship was ob- served when lung-tumor frequency was calculated as a function of dose rate, measured as the retained lung burden at the end of inhalation exposure. The fre- quency of nonmalignant lung tumors did not show a linear correlation when examined as a function of lung burden but was biased toward low lung burden. In addition to direct pulmonary toxicity, there is a potential for activation of an inflammatory response, release of inflammatory mediators, and lung in- jury. Secondary injury is discussed in Chapter 7. SUMMARY In animal studies, pulmonary toxicity was reported after exposure to ura- nium tetrafluoride and uranium hexafluoride, but uranium dioxide and triura- nium octaoxide were not associated with acute lung injury. Pulmonary fibrosis was reported in monkeys exposed to uranium dioxide dust at 5 mg/m3 for 5 y.
Toxic Effects of Uranium on the Lungs 47 On the basis of the data reviewed here, the committee concludes that acute exposure to low concentrations of insoluble uranium compounds does not pro- duce acute lung injury although chronic exposure to naturally occurring uranium dioxide dust is capable of producing pulmonary fibrosis.